WO1995008535A1 - 4-alkylamino-1-phenoxyalkyl piperidines en tant qu'agents anti-inflammatoires, antiallergiques et immunomodulateurs - Google Patents

4-alkylamino-1-phenoxyalkyl piperidines en tant qu'agents anti-inflammatoires, antiallergiques et immunomodulateurs Download PDF

Info

Publication number
WO1995008535A1
WO1995008535A1 PCT/EP1994/003121 EP9403121W WO9508535A1 WO 1995008535 A1 WO1995008535 A1 WO 1995008535A1 EP 9403121 W EP9403121 W EP 9403121W WO 9508535 A1 WO9508535 A1 WO 9508535A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
alk
compound
piperidine
compounds
Prior art date
Application number
PCT/EP1994/003121
Other languages
English (en)
Inventor
Paul Rafferty
Gerald Bernard Tometzki
Original Assignee
Knoll Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Knoll Ag filed Critical Knoll Ag
Priority to JP7509553A priority Critical patent/JPH09505274A/ja
Priority to DE69404158T priority patent/DE69404158T2/de
Priority to EP94927625A priority patent/EP0720602B1/fr
Priority to US08/615,202 priority patent/US5760035A/en
Priority to AU76973/94A priority patent/AU7697394A/en
Publication of WO1995008535A1 publication Critical patent/WO1995008535A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • This invention relates to novel substituted arninoalkyl-1- (aryloxyal yl)piperidine compounds having therapeutic activity useful in treating conditions 5 associated with inflammation, allergy or the immune system, to therapeutic compositions containing these novel compounds and to processes for preparing these novel compounds.
  • NSAIA non-steroidal anti- inflammatory agents
  • NSAIA non-steroidal anti- inflammatory agents
  • Many existing NSAIA are unsuitable for use by asthmatics.
  • the compounds may be useful in the treatment of asthma.
  • R 2 is a hydrogen or a lower alkyl radical
  • R3 is the acyl residue of an organic alkylcarboxylic acid having up to 10 carbon atoms
  • R 4 is an optionally substituted phenyl radical
  • X is C2_3 alkylene radical optionally substituted by one or more lower alkyl radicals
  • n is 2- or 2
  • Ar is inter alia optionally substituted phenyl; are useful for treating hypertension.
  • Compounds of formula A in which R3 represents hydrogen are disclosed as intermediates but no pharmacological activity is reported for these compounds.
  • R-*_ is a hydrogen atom, an acyl radical or an optionally substituted aryl radical
  • R2 is a hydroxymethyl radical, a cyano group, an amidino group which is optionally substituted by hydroxyl, a 1H- tetrazol-5-yl radical or a -CO-R3 radical
  • R3 is a hydroxyl group, a lower alkoxy radical or an amino group which is optionally substituted by a lH-tetrazol-1-yl radical
  • X is an imino group or an oxymethyl radical
  • A is an alkylene radical containing 2 to 4 carbon atoms and B is a valency bond or a 4-hydroxypyrimidin-2, 5-diyl radical; have an anti-allergic action, especially due to their strongly anti-histaminic action.
  • the compounds are also alleged to have anti-oedematous and anti ⁇ phlogistic effectiveness.
  • R-*_ represents a straight- or branched-chain, saturated or unsaturated aliphatic hydrocarbon group containing at least two carbon atoms, a phenoxyalkyl group, an aralkyl group or an aralkenyl group
  • R2 represents a 'straight- or branched-chain, saturated or unsaturated aliphatic hydrocarbon group, an aralkyl group, or an unsubstituted or substituted aromatic or aromatically unsaturated heterocyclic group
  • R and R4 which may be the same or different, each represents an alkyl or aralkyl group or, jointly, together with the adjacent nitrogen atom, represents a heterocyclic group which may contain a further hetero atom
  • R5 represents a hydrogen atom, or a lower alkyl group in the 3-position; exhibit analgesic activity and alleges that the compounds have spasmolytic, sedative and/or cough-soothing activity. However these compounds also exhibit cardiovascular activity which is undesirable.
  • EP 520,882 discloses the use of 4-aminomethyl-l- [2-
  • EP 526,342 discloses the use of 4- (2-aminoethyl) -1- [2- (4-fluorophenoxy)ethyl]p;peridine as a chemical intermediate. No pharmacological activity is reported for this compound.
  • Japanese Laid Open Patent Application No. 63-154683 (1988) discloses that certain pyridazinones are useful as heart stimulants. This application generically discloses intermediate compounds of formula D
  • R2, R3 and R 4 independently represent hydrogen, a C* ] __5 alkoxy group or hydroxy; m and n are each whole numbers from 0-4' and X is oxygen, sulphur, N(R 5 ) (in which R5 is hydrogen or a C-*__5 alkoxy group) or a single bond with the proviso that m is only 0 when X is a single bond.
  • No specific examples are given of compounds of formula D in which X represents oxygen and no pharmacological activity is reported for compounds of formula D.
  • the present invention provides novel compounds of formula I
  • R- j _, R2 and R independently represent hydrogen, hydroxy, halo, a C- j __g alkyl group (optionally substituted by one or more halogen atoms) or a c i- ⁇ alkoxy group (optionally substituted by one or more halogen atoms);
  • ALK 1 represents a C 2 _ alkylene chain optionally substituted by one or more * j __2 alkyl groups;
  • Y represents a piperidine ring which is attached through
  • R4 represents hydrogen or a - j __ ⁇ alkyl group
  • the broken line in represents a bond, so that a double bond connects Y and CR4, or is absent and the free valency on Y is taken up by hydrogen and the free valency on CR4 is taken up by hydrogen or a C- ] __ 4 alkyl group;
  • ALK ⁇ is absent or represents a C-*__ 4 alkylene chain optionally substituted by one or more -*__2 alkyl groups;
  • R5 and Rg independently represent hydrogen, a C--__g alkyl group, a phenyl C- j __ 4 alkyl group (in which the phenyl ring is optionally substituted by one or more of the following: a C- j __ 4 alkyl group, a C- ] __4 alkoxy group, halo or trifluoromethyl) or R5 and Rg together with the nitrogen atom to which they are attached represent a saturated 3-7 me bered heterocyclic ring, optionally containing sulphur, oxygen or an additional nitrogen atom, wherein the ring is optionally substituted by one or more C* j __ 4 alkyl groups;
  • a group containing a chain of three or more carbon atoms may be straight or branched, for example propyl includes n-propyl and isopropyl and butyl includes n-butyl, sec-butyl, isobutyl and tert-butyl .
  • R- j _, R2 and R3 independently represent hydrogen, hydroxy, halo (for example bro o, chloro or fluoro) , trifluoro ⁇ methyl, a - j __4 alkyl group (for example methyl, ethyl, propyl or butyl) or a C- j __ 4 alkoxy group (for example methoxy, ethoxy, propoxy or butoxy) ;
  • R5 represents hydrogen, a - j __ 4 alkyl group (for example methyl, ethyl, propyl or butyl) or a phenyl - j __ 4 alkyl group [(in which the phenyl ring is optionally substituted by one or more of the following: a C- j __ 4 alkyl group, a - j __ 4 alkoxy group or halo) for example benzyl or phenethyl] ; and
  • Rg represents a -*__4 alkyl group (for example methyl, ethyl, propyl or butyl) or a phenyl C- ⁇ _ ⁇ alkyl group [(in which the phenyl ring is optionally substituted by one or more of the following: a ⁇ _ ⁇ alkyl group, a C* ] __4 alkoxy group or halo) for example benzyl or phenethyl] ; or R ⁇ and Rg together with the nitrogen atom to which they are attached represent a pyrrolidine ring, a piperidine ring or a morpholine ring.
  • R- j _ represents hydrogen, halo, a C- j __4 alkyl group or a C-
  • R2 represents hydrogen, halo, a C- ] __4 alkyl group or a - ] __4 alkoxy group;
  • R3 represents hydrogen, a - j __4 alkoxy group or hydroxy
  • R5 represents hydrogen, a C- j __4 alkyl group or a phenyl C _4 alkyl group (in which the phenyl ring is optionally substituted by one or more of the following: a C- j __4 alkyl group, a C* j __ alkoxy group or halo) ; and
  • Rg represents a C-*__4 alkyl group or a phenyl C- j __ alkyl group (in which the phenyl ring is optionally substituted by one or more of the following: a - j __4 alkyl group, a C*-__ alkoxy group or halo) ; or R ⁇ and R g together with the nitrogen atom to which they are attached represent a pyrrolidine ring, a piperidine ring or a morpholine ring.
  • R-*_, R 2 , R3, R5, Rg, and m in preferred compounds of formula III are listed below.
  • R--_ represents hydrogen, chloro, fluoro, methoxy or methyl. More preferably R j represents hydrogen, chloro, fluoro or methyl. Most preferably R-*_ represents hydrogen or chloro.
  • R 2 represents hydrogen or chloro.
  • R represents hydrogen, hydroxy or methoxy. More preferably R3 represents hydrogen.
  • R5 represents hydrogen, methyl, ethyl or propyl and Rg represents methyl, ethyl, propyl or benzyl or Re; and Rg together with the nitrogen atom to which they are attached represent a pyrrolidine ring or a piperidine ring. More preferably, R5 represents methyl and Rg represents methyl or benzyl or Rg and Rg together with the nitrogen atom to which they are attached represent a piperidine ring. Most preferably, R 5 and Rg both represent methyl.
  • m 1, 2 or 3. More preferably m represents 1 or 2. Most preferably m represents 1.
  • the compounds of formula I may form organic or inorganic salts, ''for example, the compounds of formula I may form acid addition salts with inorganic or organic acids, e.g. hydrochloric acid, hydrobromic acid, fumaric acid, tartaric acid, citric acid, sulphuric acid, hydriodic acid, phosphoric acid, maleic acid, acetic acid, succinic acid, benzoic acid, pamoic acid, palmitic acid, dodecan ' oic acid and acidic amino acids such as glutamic acid.
  • inorganic or organic acids e.g. hydrochloric acid, hydrobromic acid, fumaric acid, tartaric acid, citric acid, sulphuric acid, hydriodic acid, phosphoric acid, maleic acid, acetic acid, succinic acid, benzoic acid, pamoic acid, palmitic acid, dodecan ' oic acid and acidic amino acids such as glutamic acid.
  • Some compounds of formula I may form base addition salts, for example, with alkali metal hydroxides for example sodium hydroxide, or with aminoacids for example, lysine or arginine or with organic bases, for example meglumine. Certain compounds of formula I may exist in Zwitterionic form. It will be appreciated that all such salts, provided they are pharmaceutically acceptable may be used in therapy in place of the corresponding compounds of formula I. Such salts are prepared by reacting the compound of formula I with a suitable acid or base in a conventional manner. Such salts may also exist in the form of solvates (for example, hydrates).
  • R ⁇ and Rg may also contain at least one chiral centre, for example when R--_, R2, R3, R5 and Rg is sec-butyl.
  • a compound of formula I, or a salt thereof contains a single chiral centre it may exist in two enantiomeric forms.
  • the present invention includes individual enantiomers and mixtures of those enantiomers.
  • the enantiomers may be obtained by methods known to those skilled in- the art.
  • Such methods typically include resolution via formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallisation; resolution via formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallisation, gas-liquid or liquid chromatography; selective reaction of one enantio er by reaction with an enantiomer-specific reagent, for example, enzymatic esterification, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • enantiomers may be synthesised by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
  • a compound of formula I When a compound of formula I, or a salt thereof, contains more than one chiral centre it may exist in diastereoisomeric forms.
  • the diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example, chromatography or crystallisation and the individual enantiomers within each pair may be separated as described above.
  • the present invention includes each diastereoisomer of compounds of formula I and mixtures thereof.
  • Certain compounds of formula I may exist in more than one geometric isomeric form for example when a double bond is present between Y and C(R 4 ) .
  • the present invention includes each geometric isomer and mixtures thereof.
  • Certain compounds of formula I and their salts may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof.
  • Certain compounds of formula I may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.
  • the present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof (including the three excluded compounds) together with a pharmaceutically acceptable diluent or carrier.
  • Such pharmaceutical compositions may be used in the treatment of inflammatory and/or allergic diseases.
  • the term "active compound” denotes a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the active compound may be administered orally, rectally, parenterally, topically, ocularly, aurally, nasally, intravaginally or to the buccal cavity, to give a local and/or a systemic effect.
  • the active compounds may be administered in a prophylactic manner.
  • the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for such methods of administration.
  • the compositions may be formulated in a manner known to those skilled in the art so as to give a controlled release, for example rapid release or sustained release, of the compounds of . the present invention.
  • Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy.
  • the compositions of the invention suitably contain 0.1-90% by weight of active compound.
  • the compositions of the invention are generally prepared in unit dosage form.
  • compositions for oral administration are the preferred compositions of the invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oily suspensions.
  • the excipients used in the preparation of these compositions are the excipients known in the pharmacists' art.
  • Tablets may be prepared from a mixture of the active compound with fillers, for example, lactose or calcium phosphate, disintegrating agents, for example maize starch, lubricating agents, for example magnesium stearate, binders for example microcrystalline cellulose or polyvinyl pyrrolidone and other optional ingredients known in the art to permit tableting the mixture by known methods.
  • the tablets may, if desired, be coated using known methods and excipients which may include enteric coating using for example hydroxypropylmethyl- cellulose phthalate.
  • the tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention.
  • Such tablets may if desired be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate.
  • capsules for example hard or soft gelatin capsules containing the active compound with or without added excipients, may be prepared by known methods and, if desired, provided with enteric coatings in a known manner.
  • the contents of the capsule may be formulated using -known methods to give sustained release of the active compound.
  • Enteric coated compositions of the invention may be advantageous, depending on the nature of the active compound.
  • compositions for oral administration include, for example, aqueous suspensions containing the compound of formula I in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example sunflower oil.
  • the active compound may be formulated into granules with or without additional excipients.
  • the granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example water) before ingestion.
  • the granules may contain disintegrants (for example a pharmaceutically acceptable effervescent couple formed from an acid and a carbonate or bicarbonate salt) to facilitate dispersion in the liquid medium.
  • compositions of the invention suitable for rectal administration are the known pharmaceutical forms for such adminstration, for example suppositories with hard fat, semi-synthetic glycerides or polyethylene glycol bases.
  • Compositions of the invention suitable for parenteral administration are the known pharmaceutical forms for such administration, for example sterile suspensions in aqueous and oily media or sterile solutions in a suitable solvent.
  • compositions for topical administration may comprise a matrix in which the active compound is dispersed so that it is held in contact with the skin in order to administer the active compound transdermally.
  • the active compound may be dispersed in a cream, gel or' ointment base or applied in the form of a spray.
  • compositions of the invention suitable for inhalation via the mouth and/or the nose are the known pharmaceutical forms for such administration, for example aerosols, nebulised solutions or powders.
  • Metered dose systems known to those skilled in the art, may be used.
  • compositions suitable for application to the buccal cavity include slow dissolving tablets, troches, chewing gum, gels, pastes, powders, mouthwashes or rinses.
  • the compounds of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion or from a source of the compound placed within the body.
  • Internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may be a) liquid such as an oily solution or suspension of the compound to be infused for example in the form of a very sparingly water-soluble derivative such as a dodecanoate salt or b) solid in the form of an implanted support for example a synthetic resin or waxy material for the compound to be infused.
  • the support may be a single body containing all the compound or a series of several bodies each containing part of the compound to be delivered.
  • the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
  • the active compound may, if desired, be associated with other compatible pharmacologically active ingredients, for example: a) an analgesic (e.g. in treatment of rheumatoid arthritis), b) a ⁇ 2 agonist (e.g. in treatment of asthma) and c) a non-sedating antihistamine (e.g. in treatment of other allergic conditions) .
  • an analgesic e.g. in treatment of rheumatoid arthritis
  • a ⁇ 2 agonist e.g. in treatment of asthma
  • a non-sedating antihistamine e.g. in treatment of other allergic conditions
  • compositions containing a therapeutically effective amount of a compound of formula I may be used to treat inflammatory and/or allergic conditions in human beings.
  • the amount of the compound of formula I administered per day is in the range 0.1 to 3000 mg.
  • Specific compounds which may be incorporated into the compositions of this invention are the novel compounds disclosed above.
  • a suitable dose for enteral administration -to mammals is generally within the range 0.01-80 mg/kg/day, more usually 0.2-40 mg/kg/day given in single or divided doses.
  • a suitable dose is generally within the range 0.01-80 mg/kg/day, more usually 0.2-40 mg/kg/day given in single or divided doses or by continuous infusion. Oral administration is preferred.
  • Compounds of formula I and pharmaceutically acceptable salts thereof are indicated for use as medicaments particularly in the treatment of inflammatory and/or allergic conditions for example musculoskeletal disorders for example: rheumatoid arthritis, osteo- arthritis, systemic lupus erythematosus, muscle trauma, gout, ankylosing spondylitis, tendonitis and bursitis; respiratory disorders for example: asthma and rhinitis; gastrointestinal disorders for example: gastritis, Crohn's disease, ulcerative colitis and other inflammatory diseases of the bowel; diseases of the oral cavity for example: periodontitis and gingivitis; cutaneous disorders for example: psoriasis, urticaria, allergic skin diseases, burns, ocular inflammation and ulceris; or Alzheimer's disease.
  • Compounds of formula I and salts thereof may also be useful as analgesics and/or anti-pyretic agents.
  • the present invention also includes a method of treating inflammatory and/or allergic conditions comprising the administration of a therapeutically effective amount of a compound of formula I or a_ pharmaceutically acceptable salt thereof (including the three excluded compounds) to a mammal in need thereof.
  • the present invention provides a method of 'treating inflammatory and/or allergic conditions comprising the administration of a therapeutically effective amount of an arachidonic acid release inhibitor of formula I or a pharmaceutically acceptable salt thereof (including the three excluded compounds) to a mammal in need thereof.
  • the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof (including the three excluded compounds) in the manufacture of a medicament for use in the treatment of an inflammatory and/or allergic condition.
  • the compounds of formula I may also be indicated for use as immunomodulatory agents, generally as immunosuppressants, but some compounds, in certain disease states, may exhibit immunostimulant activity.
  • the compounds according to the invention may be useful in the treatment of diseases resulting from an aberrant immune reaction.
  • the pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof may be used to treat diseases with an immunological association for example tissue rejection, such as kidney rejection,- autoimmune diseases, such as thyroiditis and type 1 diabetes; cutaneous disorders, such as contact sensitivity, eczema and psoriasis; neoplasia, such as melanoma; and HIV infection.
  • the amount of the compound of formula I administered per day will be such as to give a therapeutic effect and is generally in the range 0.1 to 2000 mg, preferably 1 to 500 mg.
  • the present invention also includes a method of treating diseases with an immunological association, comprising the administration of a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof (including the three excluded compounds) to a mammal in need thereof.
  • the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof (including the three excluded compounds) in the manufacture of a medicament for use in the treatment of diseases with an immunological association.
  • _in vitro and _in vivo tests include, for example, the n vitro mixed lymphocyte reaction and an in vivo rat Graft versus Host (GvH) test.
  • GvH in vivo rat Graft versus Host
  • the compounds of formula I and pharmaceutically acceptable salts thereof may also be indicated for use as disease-modifying antirheumatic agents. Such activity may be demonstrated by means of in vivo tests such as the antigen induced mouse arthritis test as described in WO 93/13097.
  • _, R 2 R3 and ALK 1 are as previously defined and L- ] _ represents a leaving group, for example halo or tosyl, with a compound of formula V
  • Y, R4, ALK , Rg and Rg are as previously defined, optionally in the presence of an inert organic liquid which is preferably a solvent for the reactants, e.g. N,N-dimethylformamide, at a temperature in the range from 0°C up to the boiling point of the inert organic liquid, e.g. 0-250°C, preferably by heating at a temperature in the range 20-150°C, optionally in the presence of a base e.g. triethylamine.
  • an inert organic liquid which is preferably a solvent for the reactants, e.g. N,N-dimethylformamide, at a temperature in the range from 0°C up to the boiling point of the inert organic liquid, e.g. 0-250°C, preferably by heating at a temperature in the range 20-150°C, optionally in the presence of a base e.g. triethylamine.
  • Rg represents a group other than hydrogen
  • R 1# R 2 , R 3 , ALK 1 , Y, R 4 and ALK 2 are as initially defined and R- j _ 2 CO represents a group which on reduction yields a group Rg of formula -CH R- j _2 and R-*_-*_ represents Rg (or R* j _2 C0 to give compounds in which R and Rg are identical) , with a reducing agent, for example lithium aluminium hydride, preferably in the presence of an inert organic liquid which is preferably a solvent for the compound of formula VI, for example tetrahydrofuran, at a temperature in the range from - 50°C up to the boiling point of the inert organic liquid e.g. -50 to 200°C, preferably at a temperature in the range -10 to 150°C.
  • a reducing agent for example lithium aluminium hydride
  • R-* R 2 , R 3 , ALK 1 , Y, R 4 and ALK 2 are as initially defined and represents a group which on reduction yields -NHRg, for example benzylimino, with a reducing agent, for example sodium borohydride, preferably in the presence ⁇ f an organic liquid which is a solvent for the compound of formula VII, for example an alcohol e.g. ethanol, at a temperature in the range 0-200°C, preferably by heating at a temperature in the range 20-150°C. • '
  • R- j _, R 2 R 3 , ALK 1 , Y, R 4 , Rg and ALK 2 are as initially defined and PG* ⁇ _ represents an amine protecting group for example benzoyl e.g. by hydrolysis. Suitable methods for protecting and deprotecting amines may be found in the textbook "Protective Groups in Organic Synthesis" by T.W. Greene, John Wiley and Sons, 1981.
  • ALK , R4, Rg and Rg are as initially defined and X represents halo, or (b) a compound of formula Xb
  • R- j _g represents an alkyl group, in which Xa or Xb has been pretreated with a base, e.g. n-butyllithium, in an inert organic liquid e.g. tetrahydrofuran, and the mixture combined in an inert organic liquid e.g. tetrahydrofuran, at a temperature in the range from 0°C up to the boiling point of the inert organic liquid, e.g. 0-200°C, preferably by heating at a temperature in the range 20-150°C.
  • a base e.g. n-butyllithium
  • an inert organic liquid e.g. tetrahydrofuran
  • an inert organic liquid e.g. tetrahydrofuran
  • an inert organic liquid which is preferably a solvent for XI, for example tetrahydrofuran, '' • at a temperature in the range from 0°C up to the boiling point of the inert organic liquid e.g. 0-200°C, preferably by heating at a temperature in the range 20-150°C.
  • R- j _, R 2 , R3 , ALK 1 , R4 and ALK 2 are as initially defined and PG 2 represents an amine protecting group, for example dimethylaminomethylene or 4-chloro- ⁇ - methylbenzylidene, preferably in the presence of a base, e.g. aqueous ammonia, or an acid, e.g. a mineral or an organic acid, e.g. hydrochloric acid or acetic acid, at a temperature in the range 0-250°C, preferably by heating at a temperature in the range of 20-100°C.
  • a base e.g. aqueous ammonia
  • an acid e.g. a mineral or an organic acid, e.g. hydrochloric acid or acetic acid
  • R-*_, R 2 , R 3 , Y, R 4 , Rg and Rg are as initially defined and -(ALK 3 ) -CO- and (ALK 4 ) -CO- represent groups which on reduction give ALK 1 and ALK 2 respectively, for example using borane, in an inert organic liquid which is preferably a solvent for the compound of formula XIII, for example tetrahydrofuran, at a temperature in the range from 0°C up to the boiling point of the inert organic liquid, e.g. 0-200°C, preferably by heating at a temperature in the range 20-150°C. It will be appreciated by those skilled in the art that if an olefinic double bond is present in XIII that this bond may also be reduced.
  • R- j _, R 2 , R3, ALK 1 are as initially defined, ALK° is absent and Y represents a piperidine ring, or a pyridiniu ring having a halide counter ion, with a reducing agent, for example lithium aluminium hydride or hydrogen in the presence of a catalyst, e.g. palladium on charcoal, in an inert organic liquid which is preferably a solvent for the compound of formula XIV, for example tetrahydrofuran-, at a temperature in the range from 0°C up to the boiling point of the inert organic liquid, e.g. 0-200°C, preferably by heating at a temperature in the range 20-150°C.
  • a catalyst e.g. palladium on charcoal
  • -(ALK°)-CN represents a group which on reduction gives -CH(R 4 ) - (ALK 2 ) -NH 2 and Y 1 represents a piperidine ring, or a pyridinium ring having a halide counter ion, with a reducing agent, for example lithium aluminium hydride or hydrogen in the presence of a catalyst, e.g. palladium on charcoal, in an inert organic liquid which is preferably a solvent for the compound of formula XIV, for example tetrahydrofuran, at a temperature in the range from 0°C up to the boiling point of the inert organic liquid, e.g. 0-200°C, preferably by heating at a temperature in the range 20-150°C.
  • a reducing agent for example lithium aluminium hydride or hydrogen
  • a catalyst e.g. palladium on charcoal
  • an inert organic liquid which is preferably a solvent for the compound of formula XIV, for example t
  • R l7 R 2 , R3, ALK 1 , Y, R 4 and ALK 2 are as initially defined and Lg represents a leaving group, for example halo, with a compound of formula XXX
  • Rg and Rg are as initially defined, optionally in the presence of an inert organic liquid which is preferably a solvent for the reactants, for example N,N- dimethylformamide or tetrahydrofuran, at a temperature in the range from 0°C up to the boiling point of the inert organic liquid e.g. 0-250°C, preferably by heating at a temperature in the range 20-150°C.
  • an inert organic liquid which is preferably a solvent for the reactants, for example N,N- dimethylformamide or tetrahydrofuran
  • R- j _, R 2 and R3 are as initially defined with a compound of formula XVIII HO— (ALK 1 ) ⁇ V m
  • ALK 1 , Y, R 4 , ALK 2 , Rg and Rg are as initially defined, in the presence of a dialkyl azodicarboxylate, for example diethyl azodicarboxylate, and a phosphorus (III) reagent for example, triphenylphosphine, optionally in the presence of an inert organic liquid which is preferably a solvent, for example tetrahydrofuran, at a temperature in the range from 0°C up to the boiling point of the inert organic liquid, for example 0-250°C, preferably by heating at a temperature in the range 0-150°C.
  • a dialkyl azodicarboxylate for example diethyl azodicarboxylate
  • a phosphorus (III) reagent for example, triphenylphosphine
  • an inert organic liquid which is preferably a solvent, for example tetrahydrofuran, at a temperature in the range from 0°C up
  • R- j _, R 2 , R3 , ALK 1 , Y and R4 are as initially defined with a reducing agent, for example iron and ammonium chloride solution or hydrogen in the presence of a catalyst.
  • a reducing agent for example iron and ammonium chloride solution or hydrogen in the presence of a catalyst.
  • R- j _, R 2 and R3 are as initially defined and -(ALK') -CHO represents a group which on reaction and reduction yields a group of formula ALK 1 , optionally in the presence of an inert organic liquid which is preferably a solvent for V and XLI, for example toluene, at a temperature in the range from 0°C up to the boiling point of the inert organic liquid e.g.
  • 0-250°C preferably by heating at a temperature in the range 20-150°C, followed by reaction of the product with a reducing agent, for example sodium borohydride or sodium cyanoborohydride, optionally in the presence of an inert organic liquid which is preferably a solvent for the reactants, e.g. ethanol, at a temperature in the range 0-250°C, preferably by heating at a temperature in the range 20-150°C.
  • a reducing agent for example sodium borohydride or sodium cyanoborohydride
  • an inert organic liquid which is preferably a solvent for the reactants, e.g. ethanol
  • ALK 1 , Y, R 4 , ALK 2 , Rg and Rg are as initially defined and Lg represents a leaving group, for example halo or tosyl, optionally in the presence of an inert organic liquid, which is preferably a solvent for the reactants, for example N,N-dimethylformamide or an alcohol, at a temperature in the range 0-250°C, preferably by heating at a temperature in the range 20- 150°C, optionally in the presence of a base, for example sodium hydroxide.
  • an inert organic liquid which is preferably a solvent for the reactants, for example N,N-dimethylformamide or an alcohol, at a temperature in the range 0-250°C, preferably by heating at a temperature in the range 20- 150°C, optionally in the presence of a base, for example sodium hydroxide.
  • ALK is as initially defined and L- j _ and L 2 independently represent a leaving group which may be the same or different provided that L 2 is more labile than L- j _, for example halo or tosyl.
  • R14CO represents a hydrolysable acyl group, for example acetyl or benzoyl, for example by reaction with dilute hydrochloric acid at a temperature in the range 0-250°C, preferably by heating at a temperature in the range 20-150°C, optionally followed by basification.
  • R- j _ 2 CO is as initially defined and L3 represents a leaving group, for example halo, by methods known to those skilled in the art.
  • Y is as initially defined, with a compound of formula IV optionally in the presence of an inert organic liquid which is preferably a solvent for the reactants, at a temperature in the range 0-250°C optionally in the presence of a base, for example triethyla ine or sodium bicarbonate.
  • an inert organic liquid which is preferably a solvent for the reactants
  • Xa and Xb may be prepared by methods known to those skilled in the art for example Xa may be prepared by reacting triphenylphosphine with a compound of formula XXV
  • R 4 , ALK , R and Rg are as initially defined.
  • R 1 ; R 2 , R3 and ALK J are as initially defined and L represents a leaving group, for example halo, with a compound of formula V for example in the presence of a base, e.g. triethylamine, in an inert organic liquid, e.g. dichloromethane at a temperature in the range from 0°C up to the boiling point of the inert organic liquid, e.g. 0-200°C, preferably by heating at a temperature in the range 20-150°C.
  • a base e.g. triethylamine
  • an inert organic liquid e.g. dichloromethane
  • Rg and Rg are as initially defined, for example in an inert organic liquid, e.g. tetrahydrofuran, at a temperature in the range 0-150°C in the presence of a base, for example triethylamine, preferably by heating at a temperature in the range 20-150°C.
  • a base for example triethylamine
  • R4 A K ⁇ and PG 2 are as initially defined with a compound of IV for example in the presence of a base, e.g. triethylamine in an inert organic liquid, e.g. dichloromethane or toluene, at a temperature in the range from 0°C up to the boiling point of the inert organic liquid, e.g. 0-200°C, preferably by heating at a temperature in the range 20-150°C.
  • a base e.g. triethylamine in an inert organic liquid, e.g. dichloromethane or toluene
  • RT , R 2 , R3, ALK 1 , Y and ALK 6 are as initially defined and L 7 represents a leaving group, for example halo or tosyl, with a cyanide salt for example potassium cyanide, by methods known to those skilled in the art.
  • Ri, R 2 , R3, ALK 1 , Y, R 4 and ALK 2 are as initially defined by methods known to those skilled in the art .
  • R14, Y R4 and ALK 2 are as initially defined and Lg represents a leaving group, for example halo, with a compound of formula XXX in an analogous manner to the preparation of a compound of formula XI from a compound of formula XXVII and a compound of formula XXX.
  • Compounds of formula XX may be prepared by acylating a compound of formula XXXII
  • Ri , R 2 , R , ALK , Y, R4 and ALK ⁇ are as initially defined, with a halogenating agent, e.g. thionyl chloride, at a temperature in the range 0-200°C in the presence or absence of an inert organic liquid, e.g. chloroform, preferably by heating at a temperature in the range 20-150°C.
  • a halogenating agent e.g. thionyl chloride
  • Rig represents hydrogen for example by reaction with thionyl chloride at a temperature in the range 0-200°C in the presence or the absence of an inert organic liquid, e.g. chloroform, preferably by heating at a temperature in the range of 20-150°C.
  • an inert organic liquid e.g. chloroform
  • R14, Y # ⁇ > R4 and ALK ⁇ are as initially defined, for example, by reaction with the halogenating agent, for example thionyl chloride at a temperature in the range 0-200°C in the presence or the absence of an inert organic liquid, e.g. chloroform, preferably by heating at a temperature in the range of 20-100°C.
  • the halogenating agent for example thionyl chloride at a temperature in the range 0-200°C in the presence or the absence of an inert organic liquid, e.g. chloroform
  • Y, R4 and ALK ⁇ are as initially defined, with a compound of formula XXVI for example, by reaction in the presence of a base, e.g. triethylamine, in an inert organic liquid, e.g. dichloromethane, at a temperature in the range from 0°C up to the boiling point of the inert organic liquid, e.g. 0-200°C, preferably by heating in the range 20-150°C.
  • a base e.g. triethylamine
  • an inert organic liquid e.g. dichloromethane
  • a base e.g. triethylamine
  • an inert organic liquid e.g. methylene chloride
  • Compounds of formula XXXV may be prepared by acylating compounds of formula XXXVI by methods known to those skilled in the art for example by reacting with an acylating agent optionally in the presence of a base, e.g. triethylamine, and then reacting with base at a temperature in the range 0-100°C to cleave any 0- acylated material.
  • a base e.g. triethylamine
  • an inert organic- liquid which is preferably a solvent for the starting compound of formula I, for example an alcohol at a temperature in the range 0-250°C preferably 15-100°C, preferably at a pressure of 1 atmosphere.
  • alkylation reactions may give rise to quaternary salt by-products from which the desired product may be separated by known techniques for example distillation.
  • the compounds of formula I are antiinflammatory agents and may show therapeutic activity at a dose of 200 mg/kg or lower in standard laboratory animals.
  • the therapeutic activity of compounds of formula I has been demonstrated by Test A and one or more of Tests B, C and D. Test A was carried out in the following way: -
  • mice Female MF1 mice (weighing 20 to 25 g) were killed using a rising concentration of C0 2 . The mice were laid on their backs and the abdomens wiped with 70% alcohol. The skin was pulled back, exposing the peritoneal wall.
  • Medium A (5 ml) (see below) was injected into the peritoneal cavity of each mouse followed by approximately 1 ml of air using a 20 ml syringe and a 21G x 40 mm needle in order to form a suspension of macrophage cells. The medium and cells were then removed using a 19G x 40 mm needle. The resulting suspension was returned to a sterile beaker kept on ice. The extracts from all the mice were pooled and this pooled cell suspension was counted using a Coulter counter and adjusted to a final cell count of 1 -
  • mice 1.3 x IO 6 cells/ml prior to labelling with [ 3 H]- arachidonic acid. Typically five mice provided sufficient cells for each multiwell plate.
  • non-adherent cells were removed by washing 3 times with sterile phosphate buffered saline (PBS) .
  • PBS sterile phosphate buffered saline
  • the adherent peritoneal macrophages were then cultured for a further 24 hours in the presence or absence of drugs, in medium B (see below) at 37° in a 5% C0 2 atmosphere in order to measure the effects of drugs on the spontaneous release of arachidonic acid in the absence of stimulus.
  • medium B see below
  • supernatants were removed to give medium 1 and stored in sealed multi-well plates at 4°C prior to scintillation counting.
  • Drugs which potentiated spontaneous release of arachidonic acid (125% of controls) were deemed to be toxic at the concentration at which this phenomenon occurred.
  • the supernatants were replaced by fresh medium C containing fresh drug and a stimulus.
  • Three drugs were tested at six concentrations (100, 50, 20, 10, 5 and 1 ⁇ M) in replicates of four on each plate.
  • the other wells contained controls consisting of a positive control (e.g. dexamethasone) , medium (B) only and medium C only.
  • the percentage of arachidonic acid released was calculated using the mean values for each group of 4 wells in the following equation.
  • the value for the arachidonic acid release in the absence of stimulus (spontaneous, cpm of medium 2) from cells which had been exposed to neither stimulus nor drug was subtracted from all equivalent values (cpm media 2, stimulated with or without drug) to give the net stimulated release.
  • the percentage inhibition of arachidonic acid release caused by a drug may then be calculated using the following equation.
  • net stimulated release in Inhibition 100 - presence of drug x 100 net stimulated release in absence of drug
  • Compounds of formula I were tested at six concentrations (100, 50, 20, 10, 5 and 1 ⁇ M) and IC 50 values calculated. Compounds with IC Q values ⁇ 100 ⁇ M are considered to be active. Advantageous compounds have an ICg Q value ⁇ 50 ⁇ M.
  • ICN inactivated swine serum
  • ICN heat inactivated swine serum
  • 10 ml sodium bicarbonate 7.5% in sterile water
  • antibiotics solution 60 mg/ml benzylpenicillin + 100 mg/ l streptomycin
  • 0.72 ml heparin 5000 U/ml
  • the zymosan stimulant was prepared as follows:- zymosan (200mg) (supplied by Sigma) was added to PBS (20 ml) . The mixture was boiled for 30 minutes and the volume restored to 20ml with water. The zymosan was harvested by centrifugation at 500Xg for 5 minutes, washed twice by resuspension in PBS (10ml) and centrifugation. After the final separation, the zymosan was resuspended in 20ml PBS and stored as 1ml aliquots at -20°C.
  • Test B was carried out in the following way: Carrageenan-induced rat paw oedema test
  • mice Female rats, weight range 125-150 g were fasted overnight. One of the hind legs of each animal was marked with a line at the connection between the cuboid/navicular- and calcaneus/talus bones. Groups of six rats were orally dosed at 10 ml/kg, in random order, with a given dose of the test compound given as a solution or suspension in 10% (w/v) aqueous acacia solution.
  • a mixed lymphocyte reaction occurs when lymphocytes from two genetically dissimilar individuals, or inbred strains of mice are cultured together.
  • An MLR results in the activation and proliferation of lymphocytes, which is measured by the incorporation of radiolabelled thymidine into the cellular DNA synthesised during cell division.
  • a 'one-way' MLR is used to determine the immunosuppressive activity of test compounds m. vitro. In this reaction one population of spleen cells serves as the stimulator cells and is treated with mitomycin C to prevent cell division.
  • Spleen cells from a second allogeneic population are untreated and when mixed with the stimulator cells are able to undergo division which is measured. The degree of proliferation is measured in the presence and absence of test compound to assess the immunosuppressive activity of the compound.
  • lymphocyte proliferation assays including MLRs are well known, eg Bradley, pages 156-166, in Mishell and Shiigi, Eds. Selected Methods in Cellular Immunology (Freeman, San Francisco, 1980) ; and Battisto et al, methods in Enzymology 1987; 150: 83-91. Various slight modifications of these techniques are in use and that used herein is described in Gibb, Webber and Bowen, J Immunological Methods 1985; 81: 107-113.
  • the immunomodulant activity of compounds was determined in a mixed lymphocyte reaction in the following manner:-
  • HBSS Hanks balanced salt solution
  • the cells were sedimented again and washed twice in HBSS before resuspending in complete RPMI 1640 tissue culture medium (medium E) .
  • the C57BL/6 cells were resuspended to 9 is per spleen and a solution of mitomycin C at 400 ⁇ g/ml in medium E added to give a final concentration of 40 ⁇ g/ml.
  • lOO ⁇ l of each of the responder and stimulator cell suspensions were aliquoted into the wells of 96 well flat bottom microtitre plates containing 50 ⁇ l of test compound at an appropriate dilution (initially 50 ⁇ M diluted in medium E from a stock solution at 100 mM in dimethyl sulphoxide) giving a final test compound concentration of 10 ⁇ M (final dilution) .
  • Compounds active at this concentration were tested at further final dilution of 1 ⁇ M, 0.1 ⁇ M and 0.01 ⁇ M to determine the concentration of test compound which causes 50% inhibition of the immmune response (IC50) .
  • Tris base (20.6 g) was dissolved in distilled water (900 ml) and the pH adjusted to 7.65 with dilute hydrochloric acid. The volume was made up to 1000 ml with distilled water.
  • Ammonium chloride (8.3 g) was dissolved in distilled water (1000 ml) .
  • Tris stock solution (10 ml) and ammonium chloride stock solution (90 ml) were mixed, the pH adjusted to 7.2 with dilute hydrochloric acid and the solution filter sterilised.
  • MLR data were expressed as the percentage inhibition of lymphocyte proliferation caused by the test compound, calculated by the formula
  • test CPM thymidine incorporation by responder cells mixed with stimulator cells in the presence of test compound.
  • the final products of the Examples listed below affected the MLR at a concentration of 10 ⁇ M in at least two out of three tests.
  • concentration of test compound which causes 50% inhibition of the immune response ( Cg Q ⁇ M) for each compound is given below.
  • a precise ICg value was not determined for those examples listed as having an ICg Q of >10.
  • Example 35 36 43 45 46 ⁇ c 50 53.8 45.3 2.01 >10 >10
  • compositions of mixed solvents are given by volume.
  • Novel compounds were characterised by one or more of the following: elemental analysis, nuclear magnetic resonance, infra-red and mass spectroscopy. Temperatures are given in degrees Celsius.
  • HPLC high performance liquid chromatography
  • THF tetrahydrofuran
  • N,N-Dimethylformamide dimethyl acetal (23.3 ml) was added to 4-aminomethylpiperidine (20.0 g) in toluene
  • Example 10 In a similar manner to Example 10, a mixture of 4-aminomethyl-l- (3-phenoxypropyl)piperidine (3.25 g) , 98% formic acid (2.5 ml) and formaldehyde (2.4 ml, 35% aqueous solution), was heated on a steam bath for 3 hours to give 4-dimethylaminomethyl-1- (3-phenoxypropyl) - piperidine dihydrochloride, m.p. 244°C.
  • 2-Bromoethyl phenyl ether (4.94 g) was added to a mi x t u r e o f 4 - [ 2 - ( N_- b e n zy l - N - methylamino)ethyl] iperidine dihydrochloride (7.5 g) , DMF (50 ml) and triethylamine (13.7 ml).
  • the mixture was heated on a steam bath for 18 hours and then poured into water (300 ml) and acidified with 2M hydrochloric acid.
  • the mixture was washed with ether then basified with 2M sodium hydroxide solution and extracted with dichloromethane to give a gum.
  • Example 40 l-[2-(4- chlorophenoxy ) ethyl] -4- (2-dimethylaminoethylidene) - piperidine (Example 40) was hydrogenated to give l-[2- (4-chloro-phenoxy ) ethyl ] -4- (2-dimethylaminoethyl ) - piperidine dihydrochloride, m.p. 266-267°C.
  • Example 42 4- (2- dimethylammoethylidene) 1- [2- (4-methoxyphenoxy) ethyl] - piperidine (Example 42) was hydrogenated to give 4- (2- dimethylamino-ethyl) -1- [2- (4-methoxyphenoxy) ethyl] piperidine dihydrochloride, m.p. 254-256°C.
  • Example 28 In a similar manner to Example 28, a mixture of n-butyllithium (20 ml, 2.5M solution in hexanes) was added to a suspension of (2-dimethylaminoethyl) - triphenylphosphonium bromide (22.8 g) in THF (200 ml). The mixture was treated with 1- (4-phenoxybutyl) -4- piperidone (12.35 g)in dry THF (20 ml). The oil obtained on work up was hydrogenated in IMS at 1 atmosphere over 10% palladium charcoal over 16 hours to give 4- (2-dimethylaminoethyl) -1- (4-phenoxybutyl) - piperidine dihydrochloride, m.p. 268-270°C.
  • Example 31 In a similar manner to Example 31, a mixture of 4- (2-aminoethyl)piperidine (5.0 g) , 4'-chloro- acetophenone (6.04 g) , p-toluenesulphonic acid (catalytic amount) and toluene (100 ml) was boiled under reflux for 10 ' hours with water removal using a Dean and Stark apparatus. The mixture was cooled to ambient temperature and 2-bromoethyl phenyl ether (7.85 g) and triethylamine (5.4 ml) added. The mixture was boiled under reflux for 6 hours.
  • Acetic anhydride (8.72 g) was added with stirring to a mixture of 4-aminomethyl-l-(2- phenoxyethyl)piperidine (20.0 g) in pyridine (85 ml) containing 4-dimethylaminopyridine (catalytic amount) with cooling to maintain ambient temperature. The mixture was stirred overnight at ambient temperature and then evaporated to dryness. Water was removed by adding toluene and removing the toluene by distillation. The residue was dissolved in water (100 ml) and 2M hydrochloric acid (50 ml) .
  • the aqueous layer was basified with concentrated sodium hydroxide solution and then extracted with dichloromethane to give an oil.
  • the oil was extracted with boiling petroleum ether b.p. 60-80°C and then the extracts were combined and evaporated to dryness.
  • the residue was stirred with petroleum ether, b.p. 60-80°C (100 ml) .
  • the solution was decanted from the residue, dried and evaporated to give N-ethyl-N- [1- (2- phenoxyethyl)piperid-4-ylmethyl]acetamide.
  • n-Butyllithium (9.13 ml, 2.5M solution in hexanes) was added to a suspension of (2- dimethylaminoethyl)triphenylphosphonium bromide (9.46 g) in dry THF (60 ml) under nitrogen at 0°C over 5 minutes. The mixture was stirred at 0°C for
  • Examples 38-42 were carried out in a similar manner to Example 37 as summarised in Table 1 below.
  • a compound of formula IX in which ALK 1 represents ⁇ -(CH 2 ) 2 -, Y represents a piperidine ring which has ALK attached at the 1-position and the oxygen attached at the 4-position and Ri, R 2 and R3 are as given in Table 1, was reacted with a compound of formula Xa in which R4 represents hydrogen, ALK 2 represents methylene, X represents bromide and Rg and Rg are as given in
  • Tablets are prepared from the following ingredients.
  • the active compound, the lactose and some of the starch are de-aggregated, blended and the resulting mixture is granulated with a solution of the polyvinylpyrrolidone in ethanol.
  • the dry granulate is blended with magnesium stearate and the rest of the starch.
  • the mixture is then compressed in a tableting machine to give tablets containing 10 mg of active compound.
  • Exampl e W Exampl e W
  • Tablets are prepared by the method of the previous
  • Example. The tablets are enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol:dichloromethane (1:1).
  • suppositories 100 parts by weight of active compound is incorporated in 1300 parts by weight of semi-synthetic glycerides as the suppository base and the mixture formed into suppositories each containing 100 mg of active ingredient.
  • capsules 50 parts by weight of active compound, 300 parts by weight of lactose and 3 parts by weight of magnesium stearate are de-aggregated and blended. The mixture is filled into hard gelatin capsules, each capsule containing 50 mg of active ingredient.
  • the active compound is incorporated into the base by thorough homogenization until the drug is evenly distributed.
  • the ointment is packed into 10 g amber jars with screw-capped lined lids.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Rheumatology (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Dermatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

L'invention se rapporte à des composés de la formule (I) ainsi qu'à leurs sels acceptables sur le plan pharmaceutique, formule dans laquelle R1, et R2 et R3 représentent indépendamment hydrogène, hydroxy, halo, alcoyle ou alcoxy; ALK1 représente une chaîne alcoylène C¿2-6? facultativement substituée par un ou plusieurs groupe(s) alcoyle C1-2; Y représente un noyau pipéridine qui est attaché par l'azote à ALK?1; R¿4 représente hydrogène ou un groupe alcoyle C1-4; la ligne en pointillé représente une liaison, ou elle est absente, et la valence libre sur Y est prise par l'hydrogène, la valence libre sur CR4 étant prise par l'hydrogène ou un groupe alcoyle C1-4; ALK2 est absent ou représente une chaîne alcoylène C¿1-4? facultativement substituée par un ou plusieurs groupe(s) alcoyle C1-2; et R5 et R6 représentent indépendamment hydrogène, alcoyle, phényle, alcoyle (facultativement substitué), ou ils représentent ensemble avec l'atome d'azote auquel ils sont attachés un cycle hétérocyclique saturé ayant 3 à 7 éléments (avec une condition). Ces composés sont des agents anti-inflammatoires, antiallergiques et immunomodulateurs. L'invention concerne également des compositions renfermant ces composés ainsi que des procédés de préparation desdits composés.
PCT/EP1994/003121 1993-09-22 1994-09-16 4-alkylamino-1-phenoxyalkyl piperidines en tant qu'agents anti-inflammatoires, antiallergiques et immunomodulateurs WO1995008535A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP7509553A JPH09505274A (ja) 1993-09-22 1994-09-16 抗炎症剤、抗アレルギー剤および免疫変調剤としての４−アルキルアミノ−１−フェノキシアルキルピペリジン
DE69404158T DE69404158T2 (de) 1993-09-22 1994-09-16 4-alkylamino-1-phenoxyalkyl piperidine als antiinflammatorische, antiallergische und immunomodulierende wirkstoffe
EP94927625A EP0720602B1 (fr) 1993-09-22 1994-09-16 4-alkylamino-1-phenoxyalkyl piperidines en tant qu'agents anti-inflammatoires, antiallergiques et immunomodulateurs
US08/615,202 US5760035A (en) 1993-09-22 1994-09-16 Therapeutic agents
AU76973/94A AU7697394A (en) 1993-09-22 1994-09-16 4-alkylamino-1-phenoxyalkyl piperidines as antiinflammatory, antiallergic and immunomodulating agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB939319534A GB9319534D0 (en) 1993-09-22 1993-09-22 Therapeutic agents
GB9319534.5 1993-09-22

Publications (1)

Publication Number Publication Date
WO1995008535A1 true WO1995008535A1 (fr) 1995-03-30

Family

ID=10742328

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1994/003121 WO1995008535A1 (fr) 1993-09-22 1994-09-16 4-alkylamino-1-phenoxyalkyl piperidines en tant qu'agents anti-inflammatoires, antiallergiques et immunomodulateurs

Country Status (9)

Country Link
US (1) US5760035A (fr)
EP (1) EP0720602B1 (fr)
JP (1) JPH09505274A (fr)
AU (1) AU7697394A (fr)
DE (1) DE69404158T2 (fr)
GB (1) GB9319534D0 (fr)
IL (1) IL111016A0 (fr)
WO (1) WO1995008535A1 (fr)
ZA (1) ZA947331B (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003078395A1 (fr) * 2002-03-19 2003-09-25 Astrazeneca Ab Derives de piperidine utiles en tant que modulateurs de l'activite de recepteur de chimiokine
US7186718B2 (en) 2001-08-22 2007-03-06 Astrazeneca Ab Piperidinyl-morpholinyl derivatives as modulators of chemokine receptor activity
US7238691B2 (en) 2001-09-18 2007-07-03 Astrazeneca Ab Piperidine derivatives and their use as modulators of chemokine (especially CCR3) activity
US7307090B2 (en) 2001-07-02 2007-12-11 Astrazeneca Ab Piperidine derivatives useful as modulators of chemokine receptor activity
US7482363B2 (en) 2002-03-19 2009-01-27 Astrazeneca Ab Piperidine derivatives useful as modulators of chemokine receptor activity
US7495013B2 (en) 2003-04-01 2009-02-24 Astrazeneca Ab Chemical compounds
EA016007B1 (ru) * 2005-04-01 2012-01-30 Биопроже Лечение болезни паркинсона, обструктивного синдрома апноэ во сне, слабоумия с тельцами льюи, сосудистой деменции с помощью не содержащих имидазол алкиламиновых лигандов гистаминовых н-рецепторов
US8314127B2 (en) 2005-07-21 2012-11-20 Astrazeneca Ab Piperidine derivatives
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2772616B1 (fr) * 1997-12-24 2000-02-25 Caster Composition depigmentante
EP3468960B1 (fr) 2016-06-08 2022-03-23 GlaxoSmithKline Intellectual Property Development Limited Composés chimiques en tant qu'inhibiteurs de la voie atf4

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1052302A (fr) * 1963-04-22
US4027028A (en) * 1975-11-10 1977-05-31 Science Union Et Cie Arylethers and pharmaceutical compositions
US4348401A (en) * 1979-09-28 1982-09-07 Boehringer Mannheim Gmbh N-Phenoxyalkylpiperidine derivatives
EP0520882A1 (fr) * 1991-06-27 1992-12-30 Synthelabo Dérivés de 2-aminopyrimidine-4-carboxamide, leur préparation et leur application en thérapeutique
EP0526342A1 (fr) * 1991-07-31 1993-02-03 Adir Et Compagnie Isoquinolein-5-yl sulfonamides, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1036272A (en) * 1961-11-20 1966-07-20 Nl Combinatie Chem Ind Tertiary aryloxyalkanoyl aminoalkylamines
US3531487A (en) * 1966-10-25 1970-09-29 Hoffmann La Roche 4-(n,n-disubstituted-amino)-piperidines
GB1194505A (en) * 1968-05-21 1970-06-10 Science Union & Cie Piperidinol Derivatives and Process for Preparing Them
US4216326A (en) * 1975-01-20 1980-08-05 Sterling Drug Inc. Intermediates for preparing anti-inflammatory phenyl-lower-alkylamines
CA1082710A (fr) * 1976-03-19 1980-07-29 Jacinto Moragues Mauri Preparation d'amides aromatiques
YU41932B (en) * 1979-07-09 1988-02-29 Pfizer Process for obtaining substituted piperazines and piperidi
US4304911A (en) * 1980-11-19 1981-12-08 Sterling Drug Inc. Benzoylphenyl lower alkanoyl piperidines
US4339576A (en) * 1980-11-19 1982-07-13 Sterling Drug Inc. Anti-asthmatic, anti-allergic, anti-cholinergic, bronchodilator and anti-inflammatory 1-[(benzoylphenyl)-lower-alkyl]piperidines and analogs thereof
JPS63154683A (ja) * 1986-12-16 1988-06-27 Mitsubishi Kasei Corp ピリダジノン誘導体又はその塩類
FI95572C (fi) * 1987-06-22 1996-02-26 Eisai Co Ltd Menetelmä lääkeaineena käyttökelpoisen piperidiinijohdannaisten tai sen farmaseuttisen suolan valmistamiseksi
EP0306375A1 (fr) * 1987-08-07 1989-03-08 Synthelabo Dérivés de[(pipéridinyl-4)méthyl]-2 tétrahydro-1,2,3,4 isoquinoléine, leur préparation et leur application en thérapeutique
JP2832979B2 (ja) * 1988-02-15 1998-12-09 武田薬品工業株式会社 不飽和カルボン酸アミド誘導体
EP0343307A1 (fr) * 1988-05-26 1989-11-29 Fabrica Espanola De Productos Quimicos Y Farmaceuticos, S.A. Dérivés de 4-pipéridinealcanamine
ZA899436B (en) * 1988-12-12 1990-08-29 Ciba Geigy Piperidine derivatives
MX9100513A (es) * 1990-08-06 1992-04-01 Smith Kline French Lab Compuestos
MX9100517A (es) * 1990-08-06 1992-04-01 Smith Kline French Lab Compuestos
FR2676054B1 (fr) * 1991-05-03 1993-09-03 Sanofi Elf Nouveaux composes n-alkylenepiperidino et leurs enantiomeres, procede pour leur preparation et compositions pharmaceutiques les contenant.
FR2676053B1 (fr) * 1991-05-03 1993-08-27 Sanofi Elf Nouveaux composes dialkylenepiperidino et leurs enantiomeres, procede pour leur preparation et compositions pharmaceutiques les contenant.
HUT71886A (en) * 1992-07-17 1996-02-28 Janssen Pharmaceutica Nv 4-amino-n-(4-methyl-4-piperidinyl)-2-methoxybenzamide derivatives, pharmaceutical compositions containing-them and process for producing them

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1052302A (fr) * 1963-04-22
US4027028A (en) * 1975-11-10 1977-05-31 Science Union Et Cie Arylethers and pharmaceutical compositions
US4348401A (en) * 1979-09-28 1982-09-07 Boehringer Mannheim Gmbh N-Phenoxyalkylpiperidine derivatives
EP0520882A1 (fr) * 1991-06-27 1992-12-30 Synthelabo Dérivés de 2-aminopyrimidine-4-carboxamide, leur préparation et leur application en thérapeutique
EP0526342A1 (fr) * 1991-07-31 1993-02-03 Adir Et Compagnie Isoquinolein-5-yl sulfonamides, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN vol. 12, no. 426 (C - 542)<3273> 10 November 1988 (1988-11-10) *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7307090B2 (en) 2001-07-02 2007-12-11 Astrazeneca Ab Piperidine derivatives useful as modulators of chemokine receptor activity
US7186718B2 (en) 2001-08-22 2007-03-06 Astrazeneca Ab Piperidinyl-morpholinyl derivatives as modulators of chemokine receptor activity
US7238691B2 (en) 2001-09-18 2007-07-03 Astrazeneca Ab Piperidine derivatives and their use as modulators of chemokine (especially CCR3) activity
WO2003078395A1 (fr) * 2002-03-19 2003-09-25 Astrazeneca Ab Derives de piperidine utiles en tant que modulateurs de l'activite de recepteur de chimiokine
US7482363B2 (en) 2002-03-19 2009-01-27 Astrazeneca Ab Piperidine derivatives useful as modulators of chemokine receptor activity
US7517989B2 (en) 2002-03-19 2009-04-14 Astrazeneca Ab Piperidine derivatives useful as modulators of chemokine receptor activity
US7495013B2 (en) 2003-04-01 2009-02-24 Astrazeneca Ab Chemical compounds
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
EA016007B1 (ru) * 2005-04-01 2012-01-30 Биопроже Лечение болезни паркинсона, обструктивного синдрома апноэ во сне, слабоумия с тельцами льюи, сосудистой деменции с помощью не содержащих имидазол алкиламиновых лигандов гистаминовых н-рецепторов
US8314127B2 (en) 2005-07-21 2012-11-20 Astrazeneca Ab Piperidine derivatives

Also Published As

Publication number Publication date
DE69404158D1 (de) 1997-08-14
AU7697394A (en) 1995-04-10
EP0720602B1 (fr) 1997-07-09
EP0720602A1 (fr) 1996-07-10
IL111016A0 (en) 1995-01-24
JPH09505274A (ja) 1997-05-27
ZA947331B (en) 1995-03-22
US5760035A (en) 1998-06-02
GB9319534D0 (en) 1993-11-10
DE69404158T2 (de) 1997-10-30

Similar Documents

Publication Publication Date Title
US4885295A (en) Method of use of 3-arylcarbonyl- and 3-cycloalkyl-carbonyl-1-aminoalkyl-1H-indoles
US5612362A (en) Imidazolinone derivatives as tachykinin receptor antagonists
US7005432B2 (en) Substituted imidazol-pyridazine derivatives
US3922276A (en) 1-Substituted-4-benzylidenepiperidines
HU199794B (en) Process for producing piperidine derivatives and pharmaceutical compositions comprising such compounds
US5780642A (en) Imidazole derivatives as therapeutic agents
JPS63146874A (ja) インドール誘導体
EP0720602B1 (fr) 4-alkylamino-1-phenoxyalkyl piperidines en tant qu&#39;agents anti-inflammatoires, antiallergiques et immunomodulateurs
US5001134A (en) Piperidines, processes of preparation and medications containing them
CA1246563A (fr) 3-arylcarbonyl- et 3-cycloalcoylcarbonyl-1- aminoalcoyl-1h-indoles utiles comme analgesiques
EP0705258B1 (fr) Derives d&#39;amine azolyl-cyclique a activite immunomodulatrice
JP2009526815A (ja) １−フェネチルピペリジン誘導体及びオピオイド受容体リガンドとしてのその使用
US5547972A (en) Therapeutic agents useful for treating inflammatory diseases
AU3081792A (en) Piperidine derivatives and their use in treating psychosis
US4978664A (en) 3-arylcarbonyl- and 3-cycloalkyl-carbonyl-1-aminoalkyl-1H-indole pharmaceutical compositions
US4021564A (en) Neuroleptic piperidine compounds
EP0719773B1 (fr) Derive d&#39;imidazolidinone, son sel d&#39;addition d&#39;acide, et remede contre la demence senile
US6518282B1 (en) 4-Arylpiperidine derivatives for the treatment of pruritus
US5013732A (en) 3-arylcarbonyl- and 3-cycloalkyl-carbonyl-1-aminoalkyl-1H-indoles
US5378714A (en) Antipsychotic piperidine derivatives
JPH1171350A (ja) ヒドロキシピペリジン化合物およびその剤
WO1994024115A1 (fr) Nouveau derive de piperazine
EP0750607B1 (fr) 2-(aminoalcoxy)phenylalcoylamines presentant une activite anti-inflammatoire
US5741800A (en) Azolyl-cyclic amine derivates with immunomodulatory activity
US4248877A (en) Organic compounds

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AM AT AU BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU JP KE KG KP KR KZ LK LR LT LU LV MD MG MN MW NL NO NZ PL PT RO RU SD SE SI SK TJ TT UA US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE MW SD AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1994927625

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 08615202

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: 1994927625

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: CA

WWG Wipo information: grant in national office

Ref document number: 1994927625

Country of ref document: EP